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A potentially targetable Achilles' heel of cancer


dumbcritic
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Many of the mutations in the DNA of a cancer cell will lead to changes in the proteins expressed on it's surface and these can be recognised by the immune system as 'foreign.' As a consequence, such specific neoantigens can be targeted by different types of immunotherapies, which will attack cancer cells but shouldn't have an effect on any healthy cells.

In this trial  https://clinicaltrials.gov/ct2/show/NCT03412877  Dr. Rosenberg and his team at the US NCI will firstly look for every individuals own neoantigens. Once found they then genetic modify their T-cells to express a receptor (TCR) in order to target these. They then get infused into the patient and it's hoped they will cause the reduction and destruction of all tumours.


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dumbcritic
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One company has their own methods of identifying neoantigen-specific T-cells in the blood [1].

They are using nonviral (an undisclosed, CRISPR-based approach) and translated it into a single-step (c)GMP manufacturing process.

The product consist mainly of T-cells of the ''younger'' Tscm [2,3] and Tcm [4] phenotype and are polyfunctional [5]. The PhI trial is open [6] (melanoma, urothelial carcinoma, ovarian, colorectal, breast (HR+), or prostate).

Next year it will move to a product that has up to four TCRs, currently has an HLA catalog which enables analysis for over 99% of the population and tries to prioritise clonal neoantigens [7].

 

Refs:

1 https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31022-8

2 https://www.nature.com/articles/nm.4241

3 https://www.nature.com/articles/nm.2446

4 https://www.pnas.org/content/102/27/9571.long

5 https://cancerres.aacrjournals.org/content/79/13_Supplement/1433

6 https://clinicaltrials.gov/ct2/show/NCT03970382

7 https://science.sciencemag.org/content/351/6280/1463.long


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dumbcritic
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Another trial https://clinicaltrials.gov/ct2/show/NCT04102436


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dumbcritic
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Another company is running two trials in melanoma [1] and NSCLC [2]. In H2 they could have interim-efficacy read-outs, in Q4 2021 full clinical read-outs and in the same quarter will open PhI/II trials for follow-on indications (H&N, TNBC, bladder and/or RCC). In H1 2022 they should open registration directed trials in both melanoma and NSCLC.

 

After sequencing tumour and blood they use the PELEUS bioinformatics platform* to identify clonal neoantigens (generated early in a cancers' evolution and therefore expressed across many, if not all, subclones). Once found they selectively expand populations of both CD4+ and CD8+ T-cell subtypes which are able to target them.

 

* (This has been trained on data obtained from TRACERx. TRACERx has been the largest ever longitudinal study of tumour evolution in NSCLC and started back in '14. A network of 15 NHS clinical sites will deliver over 840 patients (30,000 biological samples collected to date) with harmonised therapeutic protocols (deep whole-exome sequencing across multi-regions and multi-times). It is more than 3X larger than the TCGA.)

 

Refs:

1 https://clinicaltrials.gov/ct2/show/NCT03997474

2 https://clinicaltrials.gov/ct2/show/NCT04032847


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dumbcritic
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Lyell Immunopharma have joined forces with PACT Pharma (see my second post) [1]. In this preclinical paper by the former they showed that engineered CAR-T cells (using a novel costimulatory domain) showed greater expansion, had better accumulation in tumours, reduced expression of exhaustion markers, such as PD-1, improved persistence, and enhanced cytokine production upon re-stimulation ex vivo compared to control products [2]. 

 

PACT is working on their own improvements, such as adding up to three neoTCRs and coreceptors [3].

 

Refs:

1 https://www.prnewswire.com/news-releases/lyell-immunopharma-and-pact-pharma-announce-research-and-clinical-development-partnership-301079239.html

2 https://www.nature.com/articles/s41586-019-1805-z

3 https://www.pactpharma.com/wp-content/uploads/2020/07/895-Sennino-CD8co-R-NeoTCR-engineered-T-cells-PACT-AACR2020.pdf


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dumbcritic
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One group has published that certain tumour-reactive CD8+ T-cells are CD39/CD103 double positive [1]. These cells have been found in many solid tumours, including melanoma, lung, renal, breast, head and neck cancer, colon, ovarian, and pancreatic. Some show a much higher frequency of these (e.g. melanoma and lung cancer 30-80%), while others have a much lower frequency (e.g. pancreatic and colorectal liver mets 2-15%). These TIL have a resident memory phenotype and are highly enriched within the tumour site(s) when compared to peripheral blood. These are enriched for cells reactive to neoantigens and/or viral associated tumour antigens (HPV+ cancers). They express high levels of exhaustion markers; PD-1, CTLA-4, TIM-3, LAG-3 but also are enriched for activation and proliferation markers (e.g. 4-1BB, Granzyme B, and Ki-67). A company can sort and culture as few as 2000-10,000 TIL and grow them to billions in a 5-week span. They plan to perform a PhI trial within the coming year [2].

Also, Nurix Therapeutics who plan to add a CBL-B inhibitor during ex vivo expansion of TIL (+/- an oral version). See the images.

Refs:
1 https://www.nature.com/articles/s41467-018-05072-0

2 http://www.agonox.com/new-page-1


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dumbcritic
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PACT Pharma expects clinical data from ten patients this quarter, plus additional as the year goes on (around six per quarter). The goal is to elucidate a path to registration trials.

The company will file 1-2 INDs per year applying innovative trial designs. These will include the first NeoTCR-P200 series products, which look to improve T-cell persistence, augment effector function, enhance metabolism, and more.

They continue with innovative cell and DNA manufacturing. The goal is to have an enhanced automation and process for improved COGS and to reduce turnaround times (to a few weeks). Also, complete design and construction to initiate a cGMP manufacturing facility with the potential for 3000 patient products annually.


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dumbcritic
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The IDSMC (Independent Data and Safety Monitoring Committee) has completed its first review of the ongoing, PhI/II CHIRON (advanced NSCLC) and THETIS (metastatic/recurrent melanoma) trials by Achilles, and has recommended that both continue as planned. Overall tolerability was generally similar to that of standard TIL products, with the lymphodepletion regimen accounting for most of the higher-grade adverse events.

Following the first evaluation by scan six-weeks post infusion, stable disease was observed in four out of the six, with progressive disease in the others. One had a reduction in the size of two of their four tumour lesions by approximately 55% and 90%. Engraftment data are currently available for four, with evidence of engraftment in two. This tumour lesion reduction and engraftment was in the patient who received a higher cell dose.

In the second half, enrollment will begin to test higher doses, and both will combine with an anti-PD-1 following infusion. In addition, two INDs will be filed to test the product in HNSCC and RCC.


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